Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

Zhang, Wen; Braun, Aaron; Bauman, Zachary M.; Olteanu, Horatiu; Madzelan, Peter; Banerjee, Ruma

doi:10.1158/0008-5472.can-04-1554

Cited by 40 publications

(36 citation statements)

References 40 publications

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“…Several studies addressed the expression profiles and polymorphisms of enzymes involved in methionine metabolism, including CBS in gastric cancer (25), cancer cell lines (26), biliary tract cancer (27), bladder cancer (28), colorectal cancer (29,30), breast cancer (31), and liver cancer (7,8). However, the molecular basis of altered methionine metabolism and its role in carcinogenesis have not been clarified and the connection is likely to be complex and dependent on the type of cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of cystathionine β-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis

Kim¹

2009

Oncol Rep

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Abstract. The cystathionine ß-synthase (CBS) gene encodes an enzyme that catalyzes the synthesis of cystathionine in the trans-sulfuration pathway and is subject to tight regulation because of its critical role in antioxidant and methylation metabolism. The expression level of CBS in 120 hepatocellular carcinoma (HCC) specimens evaluated by real-time reverse transcriptase PCR (RT-PCR) is markedly lower than in surrounding non-cancerous liver (P<0.0001). The correlation between CBS gene expression in HCC and clinicopathological parameters or survival of HCC patients was statistically analyzed in the present study. Our study demonstrated that reduced CBS expression is significantly correlated with high tumor stage (P=0.0019), high Edmondson grade (P=0.00084), and high AFP level (P=6.2x10 -5 ). Interestingly, a survival analysis showed that a significantly shorter overall survival (OS) time is observed in patients with reduced CBS expression (P=0.0022), although CBS expression was determined not to be an independent prognostic factor for OS (P=0.071) after considering tumor stage, tumor size, and AFP level. However, for the 62 patients with low AFP levels (<100 ng/ml), reduced CBS expression was found to be an independent prognostic factor for OS (P=0.0042) after considering tumor stage and tumor size. Thus, the expression level of CBS mRNA could be useful to predict clinical outcome of HCC, especially for patients with low AFP levels.

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Section: Discussionmentioning

confidence: 99%

Expression of cystathionine β-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis

Kim¹

2009

Oncol Rep

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“…Cells were washed three times with cold PBS, resuspended in PBS, and then harvested and lysed by suspending in lysis buffer as described previously (17,18). MS, CBS, and actin levels in cell extracts were determined using the respective primary and secondary antibodies and detected using the chemiluminescent horseradish peroxidase system (Sigma) as described previously (17,18). The intensity of protein bands was quantified using the Quantity One software (Bio-Rad) and normalized to the actin level in the same sample.…”

Section: Methodsmentioning

confidence: 99%

Monocyte Differentiation, Activation, and Mycobacterial Killing Are Linked to Transsulfuration-dependent Redox Metabolism

Garg

Vitvitsky

Gendelman

et al. 2006

Journal of Biological Chemistry

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Modulation of the ambient redox status by mononuclear phagocytes is central to their role in health and disease. However, little is known about the mechanism of redox regulation during mononuclear phagocyte differentiation and activation, critical cellular steps in innate immunity, and microbial clearance. An important intermediate in GSH-based redox metabolism is homocysteine, which can undergo transmethylation via methionine synthase (MS) or transsulfuration via cystathionine ␤-synthase (CBS). The transsulfuration pathway generates cysteine, the limiting reagent in GSH biosynthesis. We now demonstrate that expression of CBS and MS are strongly induced during differentiation of human monocytes and are regulated at the transcriptional and posttranscriptional levels, respectively. The changes in enzyme expression are paralleled by an ϳ150% increase in S-adenosylmethionine (accompanied by a corresponding increase in phospholipid methylation) and a similar increase in GSH. Activation with lipopolysachharide or infection with Mycobacterium smegmatis diminished expression of both enzymes to a significant extent and decreased S-adenosylmethionine concentration by ϳ30% of the control value while GSH and cysteine concentrations increased ϳ100 and 300%, respectively. Blockade of the transsulfuration pathway with propargylglycine suppressed clearance of M. smegmatis by macrophages and inhibited phagolysosomal fusion, whereas N-acetylcysteine promoted phagolysosomal fusion and enhanced mycobacterial clearance 3-fold compared with untreated cells. We posit that regulation of the transsulfuration pathway during monocyte differentiation, activation, and infection can boost host defense against invading pathogens and may represent a heretofore unrecognized antimicrobial therapeutic target.

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“…In an expression profiling survey, conducted in 2005, most cell lines of the NCI60 collection of human cancer cell exhibited increased CBS expression (assessed by Western blot analysis), with the highest expression levels noted in breast, ovarian, and renal cancer lines (146). In a more recent study, the prostate cancer cell lines LNCaP, PBH-1, and DU145 showed a marked increase in CBS expression, which correlated with increased H 2 S production (39).…”

Section: Increased Expression Of Cbs And/or Increased Production Of Hmentioning

confidence: 99%

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

Hellmich

Coletta

Chao

et al. 2015

Antioxidants & Redox Signaling

208

186

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Significance: Cancer represents a major socioeconomic problem; there is a significant need for novel therapeutic approaches targeting tumor-specific pathways. Recent Advances: In colorectal and ovarian cancers, an increase in the intratumor production of hydrogen sulfide (H 2 S) from cystathionine b-synthase (CBS) plays an important role in promoting the cellular bioenergetics, proliferation, and migration of cancer cells. It also stimulates peritumor angiogenesis inhibition or genetic silencing of CBS exerts antitumor effects both in vitro and in vivo, and potentiates the antitumor efficacy of anticancer therapeutics. Critical Issues: Recently published studies are reviewed, implicating CBS overexpression and H 2 S overproduction in tumor cells as a tumorgrowth promoting ''bioenergetic fuel'' and ''survival factor,'' followed by an overview of the experimental evidence demonstrating the anticancer effect of CBS inhibition. Next, the current state of the art of pharmacological CBS inhibitors is reviewed, with special reference to the complex pharmacological actions of aminooxyacetic acid. Finally, new experimental evidence is presented to reconcile a controversy in the literature regarding the effects of H 2 S donor on cancer cell proliferation and survival. Future Directions: From a basic science standpoint, future directions in the field include the delineation of the molecular mechanism of CBS upregulation of cancer cells and the delineation of the interactions of H 2 S with other intracellular pathways of cancer cell metabolism and proliferation. From the translational science standpoint, future directions include the translation of the recently emerging roles of H 2 S in cancer into human diagnostic and therapeutic approaches. Antioxid. Redox Signal. 22,

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Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

Cited by 40 publications

References 40 publications

Expression of cystathionine β-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis

Expression of cystathionine β-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis

Monocyte Differentiation, Activation, and Mycobacterial Killing Are Linked to Transsulfuration-dependent Redox Metabolism

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

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